Journal Article

DZNE-2025-00627

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Proliferating Microglia Exhibit Unique Transcriptional and Functional Alterations in Alzheimer's Disease.

Villacampa, N. (First author)DZNE* ; Sarlus, H.DZNE* ; Martorell, P.Extern* ; Bhalla, K. ; Gomez-Castro, S. ; Vieira-Saecker, A. ; Slutzkin, I. ; Händler, K.DZNE* ; Venegas, C. ; McManus, R.DZNE* ; Ulas, T.DZNE* ; Beyer, M.DZNE* ; Segal, E. ; Heneka, M. (Last author)DZNE*

2025
Sage Publishing London

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Please use a persistent id in citations: doi:10.1080/17590914.2025.2506406

Abstract: Proliferation of microglia represents a physiological process, which is accelerated in several neurodegenerative disorders including Alzheimer disease (AD). The effect of such neurodegeneration-associated microglial proliferation on function and disease progression remains unclear. Here, we show that proliferation results in profound alterations of cellular function by providing evidence that newly proliferated microglia show impaired beta-amyloid clearance in vivo. Through sorting of proliferating microglia of APP/PS1 mice and subsequent transcriptome analysis, we define unique proliferation-associated transcriptomic signatures that change with age and beta-amyloid accumulation and are characterized by enrichment of immune system-related pathways. Of note, we identify the DEAD-Box Helicase 3 X-Linked (DDX3X) as a key molecule to modulate microglia activation and cytokine secretion and it is expressed in the AD brain. Together, these results argue for a novel concept by which phenotypic and functional microglial changes occur longitudinally as a response to accelerated proliferation in a neurodegenerative environment.

Keyword(s): Animals (MeSH) ; Microglia: metabolism (MeSH) ; Microglia: pathology (MeSH) ; Microglia: physiology (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Cell Proliferation: physiology (MeSH) ; Mice, Transgenic (MeSH) ; Amyloid beta-Protein Precursor: genetics (MeSH) ; Amyloid beta-Protein Precursor: metabolism (MeSH) ; Mice (MeSH) ; Presenilin-1: genetics (MeSH) ; Presenilin-1: metabolism (MeSH) ; Disease Models, Animal (MeSH) ; Brain: pathology (MeSH) ; Brain: metabolism (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; DEAD-box RNA Helicases: metabolism (MeSH) ; DEAD-box RNA Helicases: genetics (MeSH) ; Mice, Inbred C57BL (MeSH) ; Humans (MeSH) ; Male (MeSH) ; Alzheimer’s disease ; inflammasome ; microglia ; proliferation ; transcriptome ; Amyloid beta-Protein Precursor ; Presenilin-1 ; Amyloid beta-Peptides ; DEAD-box RNA Helicases

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Contributing Institute(s):

1. Neuroinflammation, Biomarker (AG Heneka)
2. Technology Transfer and Industry Collaborations Unit (Tech Transfer)
3. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)
4. Translational Neuroimmunology (AG McManus)
5. Immunogenomics and Neurodegeneration (AG Beyer)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)
3. 352 - Disease Mechanisms (POF4-352) (POF4-352)
4. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2025

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